Epigenetic mechanisms have been shown to play an important role in several biological processes of importance to human health. For example, altered DNA methylation has been shown to promote oncogenesis by either hypermethylation of tumor suppressing genes or hypomethylation of tumor promoting genes. Recent observations have suggested that DNA methylation during gametogenesis and ernbryogenesis is an active process that is susceptible to errors and that these errors can in some instances be propagated to subsequent generations. The goal of this proposal is to test a specific hypothesis, namely that the fidelity of DNA methylation during spermatogenesis is altered as a function of aging and that these changes in methylation may be passed on to the offspring and produce functional changes in behavior. This question is of critical interest since several complex behavioral disorders arise in offspring in proportion to paternal age at the time of conception. These include schizophrenia, mental retardation, and Alzheimer's disease. The mechanism by which paternal age functions as a risk factor for these disorders is not understood. In this proposed series of experiments we assess whether DNA methylation changes occur in spermatogonium as a function of age and whether these changes correlate with alterations in offspring behavior. We use inbred mice as a model system because of their relatively rapid life cycle, their genetic homogeneity, and the availability of mutant mouse strains that will allow us to test specific hypotheses that may arise from these studies. We have assembled a group of collaborators who will address the basic mechanisms of the paternal age effect and a clinical investigator who will attempt to translate these findings into clinically relevant observations. [unreadable] [unreadable] [unreadable]